Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain.
Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), 28029 Madrid, Spain.
Cancer Cell. 2019 Apr 15;35(4):573-587.e6. doi: 10.1016/j.ccell.2019.03.002. Epub 2019 Apr 8.
Five-year survival for pancreatic ductal adenocarcinoma (PDAC) patients remains below 7% due to the lack of effective treatments. Here, we report that combined ablation of EGFR and c-RAF expression results in complete regression of a significant percentage of PDAC tumors driven by Kras/Trp53 mutations in genetically engineered mice. Moreover, systemic elimination of these targets induces toxicities that are well tolerated. Response to this targeted therapy correlates with transcriptional profiles that resemble those observed in human PDACs. Finally, inhibition of EGFR and c-RAF expression effectively blocked tumor progression in nine independent patient-derived xenografts carrying KRAS and TP53 mutations. These results open the door to the development of targeted therapies for PDAC patients.
由于缺乏有效的治疗方法，胰腺导管腺癌（PDAC）患者的 5 年生存率仍低于 7%。在这里，我们报告称，在基因工程小鼠中，联合消融 EGFR 和 c-RAF 的表达导致由 Kras/Trp53 突变驱动的 PDAC 肿瘤的显著百分比完全消退。此外，这些靶点的全身性消除会引起毒性反应，但这些毒性反应是可以耐受的。对这种靶向治疗的反应与在人类 PDAC 中观察到的转录谱相似。最后，抑制 EGFR 和 c-RAF 的表达可有效阻止携带 KRAS 和 TP53 突变的九个独立的患者来源异种移植瘤的肿瘤进展。这些结果为 PDAC 患者的靶向治疗的发展开辟了道路。
